Approximately 27 million people are living with a tumor in which the tumor suppressing activity of p53 has been inactivated. See e.g., Trends in Pharmacological Sciences, January 2011, Vol. 32, No. 1. The primary response to certain cell stresses is activation of p53 within the cell. Murine double minute 2 (MDM2) is an E3 ubiquitin ligase that targets p53 for ubiquitin-dependent degradation, and ensures that p53 is regulated by limiting p53 growth in unstressed cells. Disruption of the MDM2-p53 interaction leads to p53 induction and subsequent prevention of tumor formation. The generation of small molecules inhibitors of the MDM2-p53 interaction have therefore been of great interest.
One particular class of small molecules that have been of recent interest are peptide inhibitors. See e.g., PNAS, Sep. 3, 2013, Vol. 110, No. 36, E3445-E3454; Molecular Cancer Research, Vol. 1, 1001-1008, December 2003; and Trends in Pharmacological Sciences, January 2011, Vol. 32, No. 1. Although peptide scaffolds have been an integral design in potential drug candidates, peptides are typically restricted by their limited access to intracellular compartments, i.e., poor permeability. Additionally, even in instances where intracellular admission is achieved, peptides may be partially degraded, leading to incomplete presentation for target recognition.
The need therefore exists for p53-MDM2 inhibitors which have high cellular uptake and which are presented inside cells where disease-causing proteins are located.